The aims of the proposal are in accord with the mission of the Medications Development Division of NIDA to provide new treatments for substance abuse. This project aims to provide potential pharmacotherapies for cocaine abuse and is differentiated from others in this area by focussing on long-acting opioids of unique structure as the primary target molecules. In particular, long-acting kappa opioid agonists are targeted that will also display varying levels of mu-opioid efficacy as this appears to be beneficial for this therapeutic application. The lead compounds have emerged from our work on the orvinol and beta-naltrexamine series of opioid ligands. These are series with which we have extensive experience and significant SARs are already in place. As EKC is accepted as the most promising candidate evaluated so far, we are targeting ligands with a similar, but significantly improved, profile. The particular lead compounds are the orvinol M320 and the beta-naltrexamine BU91; in both cases pharmacological profile will be modified by changes to the N17-substituent and also to the C20 side chain in the orvinols and the C14 side chain in the beta-naltrexamines. Based on the known SAR and the hugely promising profile of the lead compounds, we are confident that a rational medicinal chemistry approach will allow access to compounds with the desired pharmacological profile. As part of this work, it is intended to define more completely the in vitro actions of ligands of this type, particularly their cellular signalling properties and efficacy. This will allow the generation of better predictive in vitro models of in vivo behaviour, an important goal in a drug design program. The drug evaluation program that has been put in place will allow rational decisions to be made on the progression of compounds, leading ultimately to evaluation against cocaine self-administration in the rat and monkey.